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8 Haematology
Fig 8.
https://t.me/med1917
29
The big, beefy tongue of
glossitis. Other causes of glossitis: iron (or Zn) deficiency, pellagra, contact dermatitis/ specific food
intolerances, Crohn’s disease, drugs (minocycline,
clarithromycin, some
may be the presenting feature of coeliac disease or
alcoholism.
ACE- i
), TB of the tongue. Glossitis
B
deficiency
12
Fanconi anaemia
Autosomal recessive disorder caused by mutations in key
identified), leading to defective stem cell repair & chromosomal fragility and thus
aplastic anaemia, risk of
short stature, microcephaly, syndactyly, deafness,
Ste m- cell transplant. Guido Fanconi,
orchidism.
AML
and breast ca (
BRCA2
1892– 1979
DNA
repair genes (>21
), skin pigmentation, absent radii,
IQ
, hypopituitarism, and crypt-
(S wiss paed iatr ici an).
Paroxysmal nocturnal haemoglobinuria: the darkest hour
In paroxysmal nocturnal haemoglobinuria (
syndrome), surface proteins are missing in all blood cells due to a somatic mutation
X
- linked
PIG- A
in the
that binds the surface proteins to cell membranes. This causes uncontrolled amplification of the complement system and leads to destruction of the
and release of haemoglobin into the circulation (
haemoglobinuria
biopsy (right- hand panel, showing a clone of
GPI
- anchored proteins on peripheral blood cells. This can determine the size of
of
PNH
clone and type of
the
gene. Cells lack the glycosyl- phosphatidylinositol
5
is not all that reliable. A much better test even than a marrow
GPI
deficiency (complete or partial). Most benefit from
supportive measures— but allogeneic stem cell transplantation is the only cure.
Eculizumab is a monoclonal an tibody that targets the
system. Blockade prevents activation of the complement distal pathway, reducing
PNH
, also known as Marchiafava– Micheli
(GPI)
RBC
fig
8.30
).
NB:
PNH
cells) is flow cytometric analysis
C5
protein of the complement
membrane
the phenomenon of
anchor
haemolysis, stabilizing haemoglobin, and reducing transfusion requirements.
331
Fig 8.
30
Urine and blood in
Haemolysis occurs throughout the day and night, but the urine concentrated overnight produces the dramatic change in colour.
5
In haemoglobinuria, urine dipstick will be positive for blood but microscopy of urine does not show
(thus dierentiating it from haematuria, but not myoglobinuria— where
PNH
. In this 24h urine sample, the darkest hour is before dawn.
Courtesy of the Crookston Collection.
CK
±
AST
will be high).
RBC
S
8 Haematology
An approach to haemolytic anaemia
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332
Haemolysis is the premature breakdown of
120
d. It usually happens in the reticuloendothelial system, ie macrophages of liver,
~
spleen, and bone marrow (extravascular), or less commonly in the circulation. In
sickle cell anaemia, lifespan may be only
if the bone marrow does not compensate suciently, a haemolytic anaemia results.
An approach is first to confirm haemolysis and then find the cause— try to an-
swer these four questions:
1
Is there evidence of increased red cell breakdown?
• Anaemia with normal or
• Bilirubin: unconjugated, from haem breakdown (pre- hepatic jaundice).
• Urinary urobilinogen (no urinary conjugated bilirubin).
• Serum
LDH,
2 Is there increased red cell production?
as i t is rel eased from re d cell s
• Reticulocytes, causing
polychromasia— ensure not related to recent bleeding or
3
Is the haemolysis mainly extra- or intravascular?
Extravascular haemolysis may lead to splenic hypertrophy and splenomegaly.
Features of intravascular haemolysis are:
• Fre e pl as ma h aem og lob in: re lea sed fro m
• Methaemalbuminaemia: some free Hb is broken down in the circulation to pro-
duce haem and globin; haem combines with albumin to make methaemalbumin.
• Plasma haptoglobin: mops up free plasma Hb, then removed by the liver.
• Haemoglobinuria: causes red- brown urine, in absence of red blood cells.
• Haemosiderinuria: occurs when haptoglobin- binding capacity is exceeded, and
free Hb is filtered in glomeruli, with absorption of free Hb via the renal tubules
and storage in the tubular cells as haemosiderin. This is detected in the urine in
sloughed tubular cells by Prussian blue staining ~
chronic intravascular haemolysis). Free haemoglobin or haeme in the circulation
can cause an
4
Why is there haemolysis? Causes are on p
AKI
require urgent identification include acute transfusion reaction,
botic thrombocytopenic purpura (
DAT
, fig
8.31
(
) identifies red cells coated with antibody or complement, the pres-
ence of which indicates an immune cause.
History Family history, race, jaundice, dark urine, drugs, previous anaemia, travel.
Examination Jaundice, hepatosplenomegaly, gallstones (pigmented, due to
bilirubin from haemolysis), leg ulcers (due to poor blood flow).
Tests
FBC
, reticulocytes, bilirubin,
and thin films for malaria screen if history of travel. The blood film may show
polychromasia and macrocytosis due to reticulocytes, or point to the diagnosis:
• Hypochromic microcytic anaemia (thalassaemia).
• Sickle cells (sickle cell anaemia).
• Schistocytes (fig
cause of microangiopathic haemolytic anaemia).
• Abnormal cells in haematological malignancy.
• Spherocytes (hereditary spherocytosis or autoimmune haemolytic anaemia).
• Elliptocytes (fig
• Heinz bodies, ‘bite’ cells (fig
8.33
8.39
deficiency).
Further tests (if the cause is still not obvious)
• Osmotic fragility testing will confirm the presence of membrane abnormalities
which have been identified on the film, eg in hereditary spherocytosis.
• Hb electrophoresis will detect haemoglobinopathies.
• Enzyme assays are reserved for when other causes have been excluded.
• Paroxysmal nocturnal haemoglobinuria (
p
334
blood (
).
MCV.
MCV
(reticulocytes are large immature
, trigger
DIC
, and increase risk of clotting.
TTP
LDH
, p
335
;
TTP
, haemolytic uraemic syndrome (
, p
335
; hereditary elliptocytosis).
8.35
, p
RBC
S, before their normal lifespan of
5
d. Haemolysis may be asymptomatic, but
.
RBC
EPO
RBC
S.
1
week after onset (implying a
334
. Life- threatening ones that
S) and
treatme nt etc.
DIC
, or throm-
). The direct antiglobulin (Coombs) test
, haptoglobin, urinary urobilinogen. Thick
HUS
), or other
335
; glucose- 6- phosphate dehydrogenase
PNH
) test by flow cytometry of peripheral
8 Haematology
Direct Coombs test/Direct antiglobulin test
et
to red blood cells.
solution.
https://t.me/med1917
333
Positive test result
Blood sample from a patient
with immune mediated
haemolytic anaemia: antibodies
are shown attached to
antigens on the RBC surface.
The patient’s washed
RBCs are incubated
with antihuman
antibodies
(Coombs reagent).
RBCs agglutinate:
antihuman antibodies
form links between RBCs
by binding to the human
antibodies on the RBCs.
Indirect Coombs test/Indirect antiglobulin test
Recipient’s serum
is obtained, containing
antibodies (Ig’s).
Anti-human Ig’s
(Coombs antibodies)
are added to the
Fig 8.
31
The direct Coombs test detects antibodies on
prenatal testing and before blood transfusion. It detects antibodies against
serum— serum is incubated with
Coombs test is positive.
Donor’s blood sample
is added to the tube
with serum.
Positive
test result
Agglutination of red blood
cells occurs, because
human Ig’s are attached
RBC
S of known antigenicity. If agglutination occurs, the indirect
Recipient’s Ig’s that targ
the donor’s red blood cells
form antibody-antigen
complexes.
RBC
S. The indirect Coombs test is used in
With kind permission of Aria Rad.
Antigens on the
red blood cell’s
surface
Human anti-RBC
antibody
Antihuman
antibody
(Coombs reagent)
RBC
S that are free in
8 Haematology
Causes of haemolytic anaemia
AIHA
AIHA
AIHA
AIHA
MAHA
G6PD
https://t.me/med1917
334
Acquired
1
Immune- mediated/ direct antiglobulin test + ve (Coombs test, p
• Drug- induced: causing formation of
branes (eg penicillin) or production of immune complexes (eg quinine).
• Autoimmune haemolytic anaemia (
causing mainly extravascular haemolysis and spherocytosis. Classify according
to optimal binding temperature to
T
° 37°C. : steroids/ rituximab (± splenectomy if refractory to medical therapy).
Crossmatching is dicult because of pan- agglutinating Abs.
match possible. Cold
surface complement. Causes a chronic anaemia made worse by cold, often with
Raynaud’s or acrocyanosis.
are idiopathic;
2
lymphoma), drugs (eg methyldopa), autoimmune disease (eg
may follow infection (mycoplasma;
• Paroxysmal cold haemoglobinuria: seen with viruses/ syphilis. It is caused by
Donath– Landsteiner antibodies sticking to
complement- mediated haemolysis on rewarming.
• Isoimmune: acute transfusion reaction (p
2
Direct antiglobulin/ Coombs −ve
3
B
& C; post flu and other vaccinations; drugs (piperacillin, rituximab).
hepatitis
Microangiopathic haemolytic anaemia (
culation, causing intravascular haemolysis and schistocytes (
include haemolytic uraemic syndrome (
eclampsia. Prosthetic heart valves can also cause mechanical damage.
4
Infection Malaria (p
infections can exacerbate haemolysis.
5
Paroxysmal nocturnal haemoglobinuria Very rare acquired stem cell disorder,
with chronic haemolysis (esp. at nighthaemoglobinuria,
failure + thrombophilia (can cause both arterial and venous clots). Tests: urinary
haemosiderin + ve; if suspect in Coombs −ve intravascular haemolysis, seek confirmation by flow cytometry (absence of
clonal anticomplement antibodies (eg eculizumab); stem cell transplantation.
Hereditary
1
Enzyme defects
• Glucose- 6- phosphate dehydrogenase (
zyme defect, aects
East. Most are asymptomatic, but may get oxidat ive cr ises due to glutathione
production, precipitated by drugs (eg primaquine, sulfonamides, aspirin), exposure
to Vicia faba (broad beans/ favism), or illness. In attacks, there is rapid anaemia
and jaundice. Film: bite- and blister- cells (
8
wks after crisis as young
(>
avoid precipitants (eg henna,
• Pyruvate kinase deficiency (
vival. Homozygotes have neonatal jaundice; later, haemolysis with splenomegaly ±
jaundice. Tes t s : enzy me ass ay. : often not ne eded; splen ectomy may he lp.
2
Membrane defects All are Coombs −ve and need folate; splenectomy may help.
• Hereditary spherocytosis (
formable spherical
splenomegaly, jaundice. Tests: mild if Hb >
fig
8.38
. Bilirubin (gallstones). Confirm with eosin- 5- maleimide binding test
by flow cytometry.
• Hereditary elliptocytosis (
tomatic (somewhat protects from malaria).
type (± death in utero).
• Hereditary ovalocytosis and stomatocytosis are rarer. Refer to a haematologist.
3
Haemoglobinopathy • Sickle cell disease (p
RBC
autoantibodies from binding to
; fig
8.32
): mediated by autoantibodies
RBC
S: warm
: IgG- mediated, bind at body
: IgM- mediated, bind at T° (<4°C), activating cell-
: keep warm. Chlorambucil may help. Causes: most
° causes of warm
AIHA
include lymphoproliferative disease (
EBV
).
RBC
S in the cold, causing self- limiting
345
); haemolysis of the newborn.
(2% of all
AIHA.
) Mechanical damage to
) Autoimmune hepatitis;
figs
HUS
),
TTP
(p
311
),
DIC,
pre- eclampsia, and
412
):
RBC
lysis and ‘blackwater fever’ (haemoglobinuria). All
fig 8.30, p
CD55
&
CD59
). : anticoagulation; mono-
100
million (mainly ) in Mediterranean, Africa, Middle/ Far
RBC
S may have enough enzyme so results normal). :
fig
8.37
); transfuse if severe.
AUTOSOMA L RECESSIVE
AUTOSOMAL DOMINANT
RBCS,
so trapped in spleenextravascular haemolysis. Signs:
: folic acid, splenectomy (limits haemolysis).
AUTOSOMAL DOMINANT
336
) deficiency (
X- LINKED
figs
8.35, 8.33
). Tes t s: enzyme assay
):
ATP
production causes
): prevalence: 1:
110
g/ L and reticulocytes <6%; film:
): film: fig
10
% display a more severe pheno-
8.39
). • Thalassaemia (p
333
.)
RBC
mem-
Use closest
SLE
). Cold
RBC
S in cir-
8.33, 8.31
). Causes
331
), marrow
): the chief
RBC
RBC
3000
. Less de-
. Mostly asymp-
338
).
CLL
AIHA
en-
sur-
,
8 Haematology
Fig 8.
https://t.me/med1917
32
Autoimmune haemolytic anaemia:
antibody- coated red cells undergoing phagocytosis by monocytes.
Fig 8.
34
Fibrin strands, deposited in
TTP
(p
311
), slicing up
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
© Prof. C Lawrence.
RBC
S (microangiopathy).
353(5
),
498
. Copyright
HUS
and
Fig 8.
33
Microangiopathic anaemia, eg from
DIC
: numerous cell fragments (schistocytes) are
present.
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
Fig 8.
35
A bite- cell in
Heinz body by the spleen; these are formed from
denatured Hb during oxidative crises.
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
353(5
),
498
G6PD
, after removal of a
353(5
),
498
. Copyright
. Copyright
BEWARE!
335
Fig 8.
36
Blister- cells (arrows) in
lowing removal of Heinz bodies. Also contracted
red cells (arrowheads).
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
Fig 8.
38
Hereditary spherocytosis. Osmotic
RBC
fragility tests:
solutions.
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
S show fragility in hypotonic
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
353(5
353(5
),
498
),
498
G6PD,
fol-
. Copyright
. Copyright
Fig 8.
37
Avoid henna use in
© Catherine Cartwright- Jones (artist)
Fig 8.
39
Hereditary elliptocytosis.
From t he New England Journal of Medicine, Bain, B,
‘Diagnosis from the blood smear’,
©
2005
Massachusetts Medical Society. Reprinted with
permission from Massachusetts Medical Society.
G6PD
deficiency!
and Roy Jones (photographer).
353(5
),
498
. Copyright
8 Haematology
Sickle cell anaemia
OHCS
https://t.me/med1917
336
Sickle cell anaemia is an autosomal recessive disorder in which production of abnormal
haemoglobin results in haemolysis and vaso- occlusive crises. It is most commonly seen
in people of African and African-Caribbean ethnicity, and arises from an amino acid
substitution in the gene coding for the chain (GluVal at posi tion
duction of HbS rather than HbA (HbA
have sickle cell anaemia (HbSS), and heterozygotes (HbAS) have sickle cell trait, which
causes no disability (and protects from falciparum malaria). Heterozygotes may still,
however, experience symptomatic sickling in hypoxia, eg in unpressurized aircraft or
anaesthesia (so all those of African descent need a pre- op sickle cell test).
Pathogenesis HbS polymerizes when deoxygenated, causing
ducing sickle cells, which are fragile and haemolyse, and also block small vessels.
Prevalence 1 out of every
people carry the sickle cell gene.
Tests Haemolysis is variable. Hb ≈ 60– 90g/ L, reticulocytes 10– 20%, bilirubin. Film:
sickle cells and target cells (
tinguish between HbSS and HbAS. Hb electrophoresis: confirms the diagnosis and
distinguishes
blood) to aid prompt pneumococcal prophylaxis (vaccine,
SS, AS
states, and other Hb variants. Aim for diagnosis at birth (cord
Signs/ symptoms Chronic haemolysis is usually well tolerated (except in crises; see
BOX
‘Managing sickle cell crises’).
Vaso- occlusive ‘painful’ crisis Common, due to microvascular occlusion. Often af-
fects the marrow, causing severe pain, triggered by cold, volume depletion, infection,
or hypoxia. Hands and feet are aected if <
may cause mesenteric ischaemia, mimicking an acute abdomen. Acute chest syn-
p
337
drome (
tems) are life- threatening complications.
leading to stroke, seizures, or cognitive defects. Transcranial Doppler ultrasonog-
raphy (in <
prevent this by reducing HbS. Also avascular necrosis (eg of femoral head), leg ul-
cers (
- agonists, eg phenylephrine, or aspiration of blood + irrigation with saline)
Aplastic crisis This is due to parvovirus
duction, especially
Sequestration crisis Mainly aects children as in adults the spleen becomes atro-
) and multi- organ failure (ischaemia/ infarction in multiple organ sys-
16
yr- olds) indicates risk of impending stroke, and blood transfusions can
fig
8.41
) and low- flow priapism (also seen in
RBC
phic. There is pooling of blood in the spleen ± liver, with organomegaly, severe
anaemia, and shock. Urgent transfusion is needed.
Complications • Splenic infarction occurs before 2yrs old, due to microvascular oc-
clusion, leading to functional asplenia and susceptibility to infection (
hood sickle deaths are caused this way).
CKD
necrosis,
tells us what it’s like to have sickle cell disease’).
• Pulmonary hypertension. • Cardiomyopathy. • Hepatotoxicity. • Osteoporosis.
. • Gallstones. • Retinal disease. • Iron overload (see
Management of chronic disease Should be managed by a haematologist.
• Folic acid, iron- free multivitamin ± vitamin D and calcium.
• Hydroxycarbamide if frequent crises (production of fetal haemoglobin, HbF).
Dose example:
and iron overload.
• Antibiotic (phenoxymethylpenicillin) prophylaxis and immunizations against en-
capsulated bacterial infections (
• Febrile children risk septicaemia: repeated admission may be avoided by early-
rescue outpatient antibiotics, eg ceftriaxone (eg
1
). Consider admission if Hb <50g/ L,
volume depletion, lung infiltration. Seek expert advice.
• Bone marrow transplant can be curative but there are significant risks.
20
mg/ kg/ d if e
Prevention Genetic counselling; prenatal tests (
90
can help prevent
% of deaths from sequestration crises.
and HbF are still produced). Homozygotes (SS)
2
2000
live births in the UK. Approximately 8% of black
fig
8.40
). Sickle solubility test: + ve, but does not dis-
p
169
3
yrs old leading to dactylitis. Occlusion
CNS
infarction occurs in ~10% of children,
CML
, may respond to hydration,
B19
S. Usually self- limiting <
, with sudden reduction in marrow pro-
2
wks; transfusion may be needed.
• Poor growth. • Renal infarction, papillary
• Asthma/ obstructive lung disease.
GFR
>60mL/ min. Iron chelator if chronic transfusions
p
369
).
2
WCC
doses, 50mg/ kg IV on days 0 and
<5 or >30 ×
109/ L, T° >40°C, severe pain,
pp
274– 5
6
) leading to pro-
RBC
S to deform, pro-
± penicillin V).
40
% of child-
BOX
‘A 7- year- old
). Parental education
8 Haematology
Managing sickle cell crises
ITU
https://t.me/med1917
• Give prompt, generous analgesia, eg IV opiates (p
have a personalized analgesia plan— ask them!
• Crossmatch blood, check
• Do a septic screen: blood cultures,
• Rehydrate with
• Consider starting antibiotics empirically if T° >38°, unwell, or chest signs.
• Measure
• Give simple blood transfusion if Hb or reticulocytes fall sharply. This helps oxygen-
• Exchange transfusion is res erved for those who are ra pidly worse ning: it is a pro-
PCV
, reticulocytes, liver, and spleen size twice daily.
ation, and is as good as exchange transfusion. Match blood for the blood group
antigens Rh(
C, D, E
cess where blood is removed and donor blood is given in stages. Indications: severe
chest crisis, suspected
HbS should be reduced to <
FBC
and reticu locyt e coun t.
MSU
IVI
and keep wa rm. Gi ve O2 by m ask if PaO2 or O2 sat s <95%.
±
) and Kell, to prevent alloantibody formation.
CNS
event, or multiorgan failure— when the proportion of
30
%.
575
). Most sickle patients will
Seek expert help early.
CXR
if T° or ch est si gns.
The acute chest syndrome Entails pulmonary infiltrates involving complete lung
segments, causing pain, fever, tachypnoea, wheeze, and cough. Major cause of
mortality. Incidence: ~
study needed ventilation,
old died. Prodromal painful crisis occurs ~
CXR
in 50% of patients. The chief causes of the infiltrates are fat embolism from
bone marrow or infection with Chlamydia, Mycoplasma, or viruses.
gesia, incentive spirometry, empirical antibiotics (cephalosporin + macrolide)
until culture results known. Bronchodilators (eg salbutamol,
be eective in those with wheezing or obstructive pulmonary function at presentation. Blood transfusion (exchange if severe). Take to
9.2
kPa (70mmHg) when breathing air.
above
0.1
episodes/ patient/ yr. 13% in the landmark Vichinsky
11
% had
CNS
symptoms, and 9% of those over 20 years
2.5
days before any abnormalities on
O2, anal-
p
164
) have proved to
if PaO2 cannot be kept
Patient- controlled analgesia is a good option if supportive measures and oral
1
analgesia do not control pain. Start with morphine
(paediatric dose) and try a rate of
1
boluses of
mL when needed. Check respiratory rate and
1
mL/ h, allowing the patient to deliver extra
mg/ kg in 50mL 5% glucose
GCS
every ¼h + O2 sats if
chest/ abdominal pain. Liaise with the local pain service.
337
Fig 8.
40
Sickle cell film: there are sickle cells,
target cells, and a nucleated red cell.
A 7- year- old tells us what it’s like to have sickle cell disease
‘I have been hospitalized over 50 times for complications from this disease.
To keep it controlled I started having monthly transfusions. After repeated
transfusions my body began to get too much iron so I had to start getting infusions. I was taking the medication desferal
a needle in my belly hooked up to a pump which I had to carry on my back in my
neat Spiderman backpack. I was hooked up to the machine for
days a week but it was okay I still got to play!!! I suered from pain crisis which
makes my legs and back hurt like someone is hitting me with a hammer.
You may notice that I may move slow or look tired when it is time for my blood
transfusion. That is because the transfusions are like a heartbeat for my body,
without it I can’t survive. When I’m in pain the only thing that helps is morphine. . .
I tell my mummy when she’s crying
6
This was necessary until a once- daily oral iron chelator came along: deferasirox.
© Prof. C Lawrence.
I WILL BE OK
Fig 8.
41
Leg ulcers in sickle cell disease.
6
which my mummy had to insert
© Prof. C Lawrence.
10
hours a day 5
!!’
8 Haematology
Thalassaemia
https://t.me/med1917
338
The thalassaemias are genetic diseases of unbalanced Hb synthesis, with underproduction (or no production) of one globin chain (see
of haemoglobin’). thalassaemias and thalassaemia are characterized by a reduction in - globin and - globin chains respectively. Unmatched globins precipitate, damaging
(ineective erythropoiesis) and circulation (haemolysis). This results in a variable
degree of microcytic anaemia and extramedullary haematopoiesis (
side the marrow). They are common in the Mediterranean, Africa, and Asia.
RBC
membranes, causing their destruction while in the marrow
The thalassaemias Usually caused by point mutations in - globin genes on
11
chromosome
, leading to chain production (+ ) or its absence (0). Various com-
binations of mutations are possible (eg
Tests
FBC, MCV, MCH
studies, HbA
, HbF, Hb electrophoresis, globin gene test, cardiac
2
thalassaemia minor or trait (eg /
and is usually asymptomatic. Mild, well- tolerated anaemia (Hb >
worsen in pregnancy.
thalassaemia intermedia: describes an intermediate state with moderate an-
aemia but not requiring transfusions. There may be splenomegaly. There are a variety of causes including mild homozygous thalassaemia mutations, eg
co- inheritance of thalassaemia trait with another haemoglobinopathy, eg HbC
thalassaemia (one parent has the HbC trait, and the other has
thalassaemia produces a picture similar to sickle cell anaemia.
thalassaemia major: denotes significant abnormalities in both - globin genes, and
presents in the
haematopoiesis occurs in response to anaemia, causing characteristic head shape,
eg skull bossing (
There is osteopenia (may respond to bisphosphonates). Skull
1
st year, with severe anaemia and failure to thrive. Extramedullary
figs
on end’ sign due to marrow activity. Lifelong blood transfusions are needed, with
resulting iron overload/ deposition. Thalassaemia major and intermedia are also associated with thrombotic risk. The film shows very hypochromic, microcytic cells +
target cells + nucleated
Treatment Promote fitness; healthy diet. Folic acid supplements help.
• Regular (~2– 4 weekly) lifelong transfusions to keep Hb >90g/ L, to suppress the
ineective extramedullary haematopoiesis and to allow normal growth.
overload is a big problem after ~
and hypogonadism, cardiac failure, and liver disease. Can be mitigated by iron
chelators (desferrioxamine
damage, risk of Yersinia ± deferiprone
Luspatercept is a promising new treatment that appears to reduce transfusion
requirement by improving
• Splenectomy if hypersplenism persists with increasing transfusion requirements
p
369
)— this is best avoided until >5yrs old due to risk of infections.
(
• Hormonal replacement or treatment for endocrine complications, eg diabetes
mellitus, hypothyroidism. Growth hormone treatment has had variable success.
• A histocompatible marrow transplant can oer the chance of a cure.
The thalassaemias (fig
16
chromosome
there are four genes (termed / ). The thalassaemias are
mainly caused by gene deletions. If all four genes are deleted (- - / - - ), death is
in utero (Bart’s hydrops). Here, HbBarts (
useless. HbH disease occurs if three genes are deleted (- - / - ); there may be mod-
erate anaemia and features of haemolysis: hepatosplenomegaly, leg ulcers, and
jaundice. The blood film shows formation of
chains, HbBarts, HbA, and HbA
is an asymptomatic carrier state (minor), with
clinical state is normal.
table
8.2
and
BOX
‘Structure
RBC
S made out-
0
/ 0, + / + , or + / 0).
(heterozygotes: 25– 28pg, homozygotes: <25pg), film, iron
MRI
+
; heterozygous state): this is a carrier state,
MCV
<75fL, HbA2 >3.5%, slight HbF.
8.42, 8.43
) and hepatosplenomegaly (also due to haemolysis).
RBC
s. HbF, HbA2 variable, HbA absent.
.
90
g/ L) which may
+
/ + , or
+
). Sickle cell +
X
- ray shows a ‘hair
Iron
10
yrs causing hypothyroidism, hypocalcaemia,
SC
twice weekly. SE: pain, deafness, cataracts, retinal
RBC
maturation.
8.44
) There are two separate - globin genes on each
PO
if evidence of cardiac iron overload).
3
) is present, which is physiologically
4
tetramers (= HbH) due to excess
. If two genes are deleted (- - / or - / - ), there
2
4
MCV
. With one gene deleted, the
8 Haematology
Structure of haemoglobin
https://t.me/med1917
2.5
0.5
7
10
–
97
50
Trace
50
–
90
Table 8.
2
The three main types of Hb in adult blood
Type Peptide chains % in adult blood % in fetal blood
HbA
HbA
HbF
2
2
2 2
2
2 2
Adult haemoglobin (HbA) is a tetramer of 2 - and 2 - globin chains each containing a haem group. In the first year of life, adult haemoglobin replaces fetal
haemoglobin (HbF).
It might be thought that because the molecular details of the thalassaemias are
so well worked out they represent a perfect example of the reductionist principle
at work: find out exactly what is happening within molecules, and you will be able
to explain all the manifestations of a disease. But this is not so. We have to recognize that two people with the identical mutation at their loci may have quite different diseases. Co- inheritance of other genes and conditions (eg thalassaemia)
is part of the explanation, as is the eciency of production of fetal haemoglobin.
The reasons lie beyond s imple co- segregation of genes promoting the formation of
fetal Hb. The rate of proteolysis of excess - globin chains may also be important—
as may mechanisms that have little to do with genetic or molecular events.
Fig 8.
43
Fig 8.
42
thalassaemia major: bossing due to
extramedullary haematopoiesis.
© Dr E van der Enden.
thalassaemia major: skull X- ray.
© Crookston Collection.
339
Fig 8.
44
thalassaemia showing target cells (also called Mexican hat cells)— arrow left panel.
Note also the teardrop cell on the right panel, and the
each panel). The shorter arrow on the left panel points to a Howell– Jolly body. Note that the cells
which are not target cells are rather small (microcytic). There is also poikilocytosis (poikilos is
Greek for varied— so this simply means that the red blood cells are of varied shape).
7
Thalassaemia major and intermedia are characterized by microcytic anaemia and non- immune haemolysis. Hb electrophoresis ± globin gene testing are required to confirm the diagnosis. Hb Barts (gamma
chain tetramers) or HbH (beta chain tetramers) are consistent with thalassaemia; increased HbF or HbA
are consistent with a thalassaemia syndrome but are non- specific.
2
normoblasts (nucleated red cells, one on
Courtesy of Prof. Tangün and Dr Köroğlu.
2
8 Haematology
An approach to bleeding disorders
APTT
OHCS
https://t.me/med1917
340
Primary haemostasis refers to the initial steps in clot formation, which mostly
rely on vessel wall and platelet function. Secondary haemostasis refers to the
subsequent formation of the fibrin- based clot, which mostly relies on coagulation
p
341
factors (
fect primary or secondary haemostasis. Evaluation of the patient with bleeding
). A bleeding disorder/tendency may be inherited or acquired and af-
requires a detailed personal and family history, a thorough review of medications,
physical examination, and laboratory testing.
History Ask about prior bleeding events and their severity (eg need for nasal
packing or cautery), sites (mucocutaneous platelet or vascular disorder (
deep tissues coagulatio n disorde r, re curr ent e pistax is— think of von Willebrand
WD
) or
HHT
disease (v
coagulation factor disorder or disorder of fibrinolysis), onset (since infancy/ childhood in keeping with hereditary condition), easy bruising, history of
orrhagia (up to
, timing (eg delayed bleeding after trauma/ surgery suggests
10– 30
% may have an underlying bleeding disorder) or bleeding
associated with pregnancy if female, prolonged bleeding after dental procedures/
surgery, any prior medical conditions that may predispose to bleeding (eg liver
disease, cancer,
family history, medications/ herbal supplements/
CKD
, connective tissue disorders), any history of alcohol excess,
OTC
(eg antiplatelets, vitamin E,
garlic).
Bleeding score May be useful to quantify personal bleeding history. The Inter-
national Society on Thrombosis and Haemostasis has an online bleeding assessment
https:// bleedi ngsc ore.certe.nl/
tool here:
Signs Look for petechiae/ purpura/ bruises, telangiectasias, splenomegaly, joint
WD
hypermobility, murmurs (associated with acquired v
), macroglossia (rarely oc-
curs with amyloidosis, a cause of acquired coagulation factor deficiencies).
Te st s
FBC
, film (is the platelet morphology normal?), coagulation screen (PT,
fibrinogen),
INR,
this initial screen. Tests for primary haemostasis include platelet count/ morphology ± aggregation studies, v
for secondary haemostasis include
tests of clotting function such as thromboelastography (
p
775
. Certain characteristic clotting screen abnormalities are highlighted in
table
8.3
• Prothrombin time (PT) Thromboplastin is added to test the extrinsic system. PT
is expressed as a ratio compared to control (international normalized ratio (
normal range =
by: warfarin, vitamin
• Activated partial thromboplastin time (
the intrinsic system. Tests for abnormalities in factors
range
• Thrombin time Thrombin is added to plasma to convert fibrinogen to fibrin.
Normal range:
• D- dimers are a fibrin degradation product, released from cross- linked fibrin
during fibrinolysis (
thromboembolism— deep vein thrombosis (
D
- dimers may also be raised in inflammation, eg with infection or malignancy.
U&E, LFT
S for all, with further testing depending on the results of
WF
antigen and activity, factor
PT, APTT
, thrombin time, factor assays. Newer
.
0.9– 1.2
). It tests for abnormalities in factors
K
deficiency, liver disease,
35– 45
s. Prolonged by: heparin treatment, haemophilia,
10– 15
s. Prolonged by: heparin treatment,
p
343
). This occurs during
) A contact factor is added to test
DVT
VIII
TEG
) are discussed on
DIC
DIC
I, II, V, VII, X
.
I, II, V, VIII, IX, X, XI, XII
DIC
DIC
, dysfibrinogenaemia.
, or in the presence of venous
) or pulmonary embolism (PE).
Management Depends on the underlying cause and the degree of bleeding. If
p
770
shocked, resuscitate (
disorder or a massive transfusion, discuss the need for fresh frozen plasma, cryoprecipitate, factor concentrates, or platelets with a haematologist. In
IV
steroids ±
immunoglobulin may be used. Especially in pregnancy (
). If bleeding continues in the presence of a clotting
sult an expert. Is there overdose of or need to reverse anticoagulants (
haemophiliac bleeds, consult early for coagulation factor replacement.
IM
injections.
IDA
activity. Tests
. Prolonged
. Normal
, liver disease.
ITP
(p
p99), con-
p
346
Never give
p
342
, men-
APTT,
INR
343
)? In
),
),
),
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